Journal Information
Vol. 33. Issue. 4.July 2013
Pages 443-622
Vol. 33. Issue. 4.July 2013
Pages 443-622
DOI: 10.3265/Nefrologia.pre2013.Apr.11922
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Severe hypocalcaemia post-denosumab
Hipocalcemia severa posdenosumab
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Isabel M. Martín-Baeza, Raquel Blanco-Garcíaa, Mario Alonso-Suáreza, Cynthia Cossio-Aranibara, Laura V. Beato-Cooa, Francisco Fernández-Fleminga
a Servicio de Nefrolog??a, Complexo Hospitalario Universitario de Vigo, Pontevedra,
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To the Editor:

Denosumab is a human IgG2 monoclonal antibody that binds to RANKL (receptor activator of nuclear factor KB ligand gene), thus causing a reduction in osteoclast activity. It has been approved since 2010 for use in osteoporosis and does not require adjustment in accordance with renal function, although several studies indicate an increase of hypocalcaemia in patients with renal failure (RF). It is administered subcutaneously biannually.1

We report the case of a 46-year-old woman with high blood pressure, dyslipidaemia, stage 5 chronic kidney disease (CKD), focal segmental glomerulonephritis and severe seronegative rheumatoid arthritis resistant to different drugs. Due to the presence of pathologic fractures to the pelvis, the Department of Rheumatology decided to start treatment with 60mg denosumab. She received treatment with 2.4g/12 hours sevelamer, 0.50mg Rocaltrol®: 5 tablets/week, 1 tablet/8 hours Mastical®, 266μg/15 days calcifediol, antihypertensive drugs and painkillers. The analytical data were: urea 205mg/dl, creatinine 5.95mg/dl, calcium 8.8mg/dl, albumin 3.8g/dl, intact parathyroid hormone 581pg/ml, 25-OH vitamin D 9.2ng/ml, alkaline phosphatase 221U/l.

One week after the drug was administered, we detected hypocalcaemia (6.7mg/dl corrected calcium) in a routine clinic blood test. The patient was asymptomatic and because of significant history of poor adherence to treatment, she was urged to adhere to treatment as prescribed.

Two weeks later, the patient came to the Emergency department with general weakness, dizziness, tremors and nausea. Corrected calcium of 5.2mg/dl was detected. Physical examination revealed no signs of hypocalcaemia (Trousseau or Chvostek) or peribuccal paresthesia.

It was decided to admit the patient for intravenous treatment, which yielded good clinical and laboratory results.

Bisphosphonates are commonly used to reduce bone loss but they are mainly eliminated through the kidney, and as such, their use is not recommended in patients with severe RF.2 Denosumab significantly reduces the risk of fractures3 and it has been shown to increase bone mineral density and reduce resorption markers. Furthermore, preclinical studies have revealed that, unlike bisphosphonate, it is not nephrotoxic at levels of 100μmol/l4 and is independent of the degree of RF, since its pharmacokinetic and pharmacodynamic profile does not vary significantly according to the degree of renal function.1

It has been hypothesised that patients with CKD and bone disease due to hyperparathyroidism may be at greater risk of hypocalcaemia with denosumab, since their serum calcium levels will depend to a greater extent on bone resorption mediated by the parathyroid hormone. As such, inhibition of osteoclast activity following administration of the first dose of denosumab could lead to a syndrome similar to hungry bone, with the rapid decrease in serum calcium levels due to its uptake by bone.5 At this time, calcium and vitamin D supplements are required, until the formation of osteoclasts leads to proper mineralisation.

In a study6 conducted on 46 patients with varying degrees of RF, pain in limbs and hypocalcaemia were observed as the most common adverse effects. The latter appeared in 15% of participants, with only two patients requiring hospitalisation for intravenous treatment and in only one, hypocalcaemia was symptomatic.

The use of denosumab in patients with CRF is convenient, as it requires no dose adjustment and it is not nephrotoxic; as such, its use is expected to increase. In this group of patients, we should administer appropriate calcium and vitamin D supplements before beginning treatment with denosumab, in addition to monitoring these parameters in the laboratory after treatment begins, since a non-negligible number of patients will develop hypocalcaemia, which will be asymptomatic in the majority of cases.

 

Conflicts of interest

 

The authors declare that they have no conflicts of interest related to the contents of this article.

Bibliography
[1]
Prolia (denosumab) product monograph. Mississauga. ON: Amgen Canada Inc; 2011.
[2]
Perazella MA, Markowitz GS. Biphosphonate nephrotoxicity. Kidney Int 2008;74:1385-93. [Pubmed]
[3]
Cummings SR, San Mart??n J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-65. [Pubmed]
[4]
Padagas J, Colloton M, Shalhoub V, Kostenuik P, Morony S, Munyakazi L, et al. The receptor activator of nuclear factor-kappaB ligand inhibitor osteoprotegerin is a bone-protective agent in a rat model of chronic renal insufficiency and hyperparathyroidism. Calcif Tissue Int 2006;78:35-44. [Pubmed]
[5]
Westenfeld R, Ketteler M, Brandenburg VM. Anti-RANKL therapy-implications for the bone-vascular-axis in CKD? Denosumab in post-menopausal women with various low bone mineral density. Nephrol Dial Transplant 2006;21(8):2075-7. [Pubmed]
[6]
Block GA, Bone HG, Fang L, Lee E, Padhi D. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res 2012;27:1471-9. [Pubmed]
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